PROJECT SUMMARY/ABSTRACT The goal of this resubmission application is to train David Y. Oh, MD PhD, a medical oncologist and immunologist, providing him with the skills to become an independently funded laboratory investigator studying immune-related adverse events (IRAEs) after checkpoint inhibitors (CPIs). CPIs are cancer immunotherapies that activate anti-tumor immune responses leading to improved survival in several cancers, but also trigger IRAEs which are autoimmune responses against normal tissues that represent an increasing source of morbidity for cancer patients. The proposed training plan incorporates didactic and practical experience to provide a foundation in the following areas which complement his existing expertise and are critical to accomplishing his research goals: (1) fundamental B cell biology including B cell-driven autoimmunity and methods for autoantibody discovery and validation, (2) next-generation sequencing methods and analysis including single-cell approaches appropriate for human patient samples, (3) methods in clinical trial design including biostatistics and correlative science. The research plan addresses key limitations in our understanding of IRAE mechanisms by studying both cellular (T cell) as well as humoral (B cell) responses to autoantigens during IRAEs. By studying IRAE tissues, the proposed research will identify and validate the specific immune responses that may be directed towards tissue-specific autoantigens. Dr. Oh?s hypothesis is that autoimmune responses in IRAE-affected tissues are newly induced by CPIs and not present before treatment, and the tissue autoantigens responsible for IRAEs are targeted by a distinct subset of tissue-resident T cells and by specific autoantibodies. The Aims of the proposed research are: (1) to dissect the antigenic and functional profile of autoreactive T cells that are enriched in IRAE-affected tissues, and (2) to discover and validate autoantibody responses to tissue-specific autoantigens that are associated with IRAEs. The training and research plan encompass a structured combination of formal coursework, tutorials, mentorship, and hands-on research experience within the dynamic environment of the University of California, San Francisco, a renowned center for basic and translational research. Dr. Oh?s training will be conducted under the mentorship of Dr. Lawrence Fong, a leading translational researcher in cancer immunotherapies who co-directs the Parker Institute for Cancer Immunotherapy at UCSF, and a distinguished advisory committee of physician-scientists with extensive mentorship experience and expertise in each area corresponding to Dr. Oh?s training and research aims. The intermediate goal of this proposal is to identify IRAE- specific immune responses that will be the basis for an R01. The long-term goal of this award is to provide the skills to enable Dr. Oh to become a leader in mechanistic studies of IRAE samples from immunotherapy-treated patients using novel approaches, yielding clinically useful biomarkers and targets for intervention to be validated in larger clinical trials.